In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 3 ( 2021-3), p. 597-613
Abstract:
The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular protein degradation mechanisms. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood. The first mouse model of podocyte-specific proteasome impairment revealed that UPS plays important roles in podocyte homeostasis, inducing p53-mediated apoptosis and mTOR-mediated autophagy suppression. The podocytes with impaired proteasomes exhibited characteristic features of aging and increase in a marker of aging. Our data suggest that proteasome impairment in podocytes leads to CKD and show that antioxidants and autophagy activators could be therapeutic agents for age-dependent CKD. Background The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal system (APLS) are major intracellular degradation procedures. The importance of the APLS in podocytes is established, but the role of the UPS is not well understood. Methods To investigate the role of the UPS in podocytes, mice were generated that had deletion of Rpt3 ( Rpt3 pdKO ), which encodes an essential regulatory subunit required for construction of the 26S proteasome and its deubiquitinating function. Results Rpt3 pdKO mice showed albuminuria and glomerulosclerosis, leading to CKD. Impairment of proteasome function caused accumulation of ubiquitinated proteins and of oxidative modified proteins, and it induced podocyte apoptosis. Although impairment of proteasome function normally induces autophagic activity, the number of autophagosomes was lower in podocytes of Rpt 3 pdKO mice than in control mice, suggesting the autophagic activity was suppressed in podocytes with impairment of proteasome function. In an in vitro study, antioxidant apocynin and autophagy activator rapamycin suppressed podocyte apoptosis induced by proteasome inhibition. Moreover, rapamycin ameliorated the glomerular injury in the Rpt3 pdKO mice. The accumulation of ubiquitinated proteins and of oxidative modified proteins, which were detected in the podocytes of Rpt3 pdKO mice, is a characteristic feature of aging. An aging marker was increased in the podocytes of Rpt3 pdKO mice, suggesting that impairment of proteasome function promoted signs of aging in podocytes. Conclusions Impairment of proteasome function in podocytes led to CKD, and antioxidants and autophagy activators can be therapeutic agents for age-dependent CKD.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2019101025
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
Permalink